Patents and patent applications cited above disclose basic aspects of transdermal delivery of drugs by electrical power patches on the patient's skin. Other U.S. and foreign patents also disclose transdermal electrical, and medical effects, as follows:
______________________________________ U.S. Pat. No. 385,556 2,267,162 3,163,166 486,902 2,493,155 3,289,671 588,479 2,784,715 3,547,107 3,677,268 4,239,052 4,367,745 4,008,721 4,243,052 4,367,745 4,141,358 4,273,135 4,406,658 4,164,226 4,290,878 4,419,019 4,166,457 4,325,367 4,474,570 4,239,046 4,362,645 Foreign Patents EPA 58,920 DE 2,902,021.83 UK 2,104,388 EPA 60,452 DE 3,225,748 ______________________________________
None of these references, however, show the effective administration of protein drugs; especially high molecular weight proteins such as insulin, renin, corticortropin, calcitonin, and glucogon with structures having more than about 20 polypeptide units and molecular weights up to 40,000 daltons.
A paper entitled "Prevention of Insulin Self-Association and Surface Adsorption" by Sato, Ebert, and Kim in the Journal of Pharmaceutical Sciences 72, No. 3, 228-232, Mar. 1983 discusses the association of insulin in water to dimers, tetramers, hexamers, and higher aggregates and consequent adsorption of these polymers onto plastic surfaces such as polyurethane, silicone, rubber, and cellulose under high shear and in the presence of additives such as lysine, ethylenediaminetetraacetic acid salts, and urea.
The ionophoresis of conventional commercial insulin is termed "meaningless" with "no significant differences in changing blood glucose levels" in a paper by Stephen, Peterlenz, and Jacobsen in Biomedical Biochemical Acta 5, 553-558 (1984) experimenting on eight human volunteers. One pig was treated with an unspecified, modified, highly ionized, predominately monomeric, derivative of insulin for 20 minutes followed by a drop in blood sugar. This publication states that "a new ionized form of insulin must be synthesized" in order for ionophoresis to be possible and states the permeability of human skin to high molecular weight polymers to be "questionable". Other difficulties discussed in this paper are the association of commercial insulin rendering the impermeability to insulin of human skin as "almost certain" and the weak ionization of insulin as "mitigating against successful transcutaneous electronic (sic) transfer of the drug".